Anterior Skull Base Tumors PDF

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Nicolai P, Bradley PJ (eds): Anterior Skull Base Tumors. Adv Otorhinolaryngol. Basel, Karger, 2020, vol 84, pp 168–184 (DOI: 10.1159/000457936) Neuroendocrine Carcinoma and Sinonasal Undifferentiated Carcinoma Ahmed S. Abdelmeguid a, b Diana Bell a, c Ehab Y. Hanna a       a   Department of Head and...

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Nicolai P, Bradley PJ (eds): Anterior Skull Base Tumors. Adv Otorhinolaryngol. Basel, Karger, 2020, vol 84, pp 168–184 (DOI: 10.1159/000457936)

Neuroendocrine Carcinoma and Sinonasal Undifferentiated Carcinoma Ahmed S. Abdelmeguid a, b Diana Bell a, c Ehab Y. Hanna a a Department of Head and Neck Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; b Department of Otolaryngology Head and Neck Surgery, Faculty of Medicine, Mansoura University, Mansoura, Egypt; c Department of Pathology, Division of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Sinonasal malignancies are uncommon, representing 1% of all neoplasms. A wide spectrum of malignant neoplasms arise from the sinonasal and skull base regions; the majority of these tumors are poorly or undifferentiated tumors manifesting overlapping features that result in diagnostic challenges. Sinonasal neuroendocrine carcinoma (SNEC) and sinonasal undifferentiated carcinoma (SNUC) are types of sinonasal neuroendocrine tumor, together with olfactory neuroblastoma. They share overlapping clinical, radiological, and histopathological features, albeit with variability in behavior and prognosis between each other. The literature is at variance regarding the appropriate management strategy of these tumors due to their rarity and difficulty in establishing the correct diagnosis. In recent years progress has been made in the diagnostic techniques and treatment strategies implemented for these tumors. Here we provide a comprehensive review of the recent literature, focusing on the recent advances in histopathological and ancillary diagnosis, and different treatment options for SNEC and © 2020 S. Karger AG, Basel SNUC.

Sinonasal tumors with neuroendocrine differentiation are a rare group of neoplasms that represents only 5% of all sinonasal malignancies [1]. Several of the malignant tumors of the sinonasal tract may present with an undifferentiated or poorly differentiated morphology, being composed of small to medium and large size, round or polygonal atypical cells. Overall, these lesions pose significant diagnostic difficulties for the surgical pathologist, especially in the limited biopsy material, but their correct classification by means of histology, immunohistochemistry, or molecular biology is becoming increasingly important for initiating an appropriate treatment strategy. A broad distinction should be made between tumors of neuroectodermal origin, like olfactory neuroblastoma (ONB), and those of epithelial origin, including sinonasal neuroendocrine carcinomas (SNECs; Fig. 1) [2]. It has been shown that tumor behavior varies markedly between the various entities of sinonasal tumors with neuroendocrine differentiation [3]. For ONB, given their less Downloaded by: Stanford Univ. Med. Center 35.203.130.101 - 8/28/2020 5:04:02 PM

Abstract

STND

Neuroectodermal

Origin

ONB

Epithelial

Differentiation Well/ moderate

Poor

SNEC ■ carcinoid ■ atypical carcinoid

aggressive nature, a well-defined treatment strategy including surgery with or without postoperative radiotherapy yields a reasonable outcome [4, 5]. However, for other SNECs no clear guidelines are available and treatment outcome remains both variable and poor. Individual studies have shown large differences in response to treatment and prognosis between different subtypes of SNEC and sinonasal undifferentiated carcinoma (SNUC) [6]. While valuable, these studies included a small number of patients due to the rarity of these tumors. The aim of this review is to provide insight into the recent advances in diagnosis and different treatment options for SNEC and SNUC.

Neuroendocrine Carcinoma

The most common location of neuroendocrine carcinoma (NEC) of the head and neck is the larynx followed by the salivary glands. SNEC is extremely rare and less than 100 cases have been reported in the medical literature [6]. It was first described in 1982 by Silva et al. [7].

NEC and SNUC

LCNEC SNUC

SmCNEC

The general diagnosis of sinonasal neuroendocrine neoplasms includes: morphological neuroendocrine features (e.g., stippled/“salt and pepper” chromatin, rosette formation, organoid and trabecular growth), presence of some degree of epithelial differentiation evidenced by cytokeratin expression, and phenotypical expression of neuroendocrine markers such as CD56/N-CAM (widespread) with synaptophysin and/or chromogranin (focal/variable) [8]. SNEC is a true neuroendocrine tumor that should meet all these diagnostic criteria. On the other hand, SNUC usually lacks the evidence of neuroendocrine markers, although SNUC may occasionally demonstrate some focal positivity to these markers [9]. NECs are characterized by the presence of neurosecretory granules with absence of the neurofibrillary background that is usually found in ONB [1]. General features of NEC include the presence of nests, ribbons, festoons, glands, rosettes, and solid patterns. Papillary, pseudopapillary, and fascicular patterns are uncommon findings. Tumor cells are round, polyhedral, or spindle-shaped cells with granular, eosinophilic,

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Nicolai P, Bradley PJ (eds): Anterior Skull Base Tumors. Adv Otorhinolaryngol. Basel, Karger, 2020, vol 84, pp 168–184 (DOI: 10.1159/000457936)

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Fig. 1. Categorical classification of sinonasal tumors with neuroendocrine differentiation (STND).

Cell size

a

amphophilic, or oncocytic cytoplasm. Nuclei are small and hyperchromatic or intermediate to large with coarse granular or speckled chromatin [10]. NECs are divided into carcinoids and atypical carcinoids, small cell type (SmCNEC), and large cell type (LCNECs), reflecting the lung neuroendocrine neoplasm [11]. Sinonasal well- and moderately differentiated NEC are extremely rare, which might be related to underreporting or inclusion under other non-descriptive NEC [8]. Well-differentiated NEC is similar to carcinoid tumors of other sites. It is characterized by a bland cytology, absence of necrosis, low mitotic figures 20%; however, it is not used for either grading or prognosis [8, 10] (Fig. 4). It is very important for management and prognosis to differentiate SNEC from other histologically similar tumors. Other tumors that can be included in the differential diagnosis of SmCNEC include lymphoma, melanoma, rhabdomyosarcoma, SNUC, ONB, Ewing’s/PNET, NUT midline carcinoma, and desmoplastic small round cell tumor [8, 10] (Fig.  5). Rhabdomyosarcoma may demonstrate focal positivity to neuroendocrine markers and cytokeratins; however, it is

a

b

Fig. 5. Ancillary work-up algorithm for undifferentiated skull base tumors. a Initial panel of immunohistochemical markers. b Ancillary immunohistochemical and molecular markers and diagnoses. ES/PNET, Ewing sarcoma/peripheral neuroectodermal tumor; NEC, neuroendocrine carcinoma; ONB, olfactory neuroblastoma; Rhabdo, rhabdomyosarcoma; SCC: Squamous carcinoma; SNUC, sinonasal undifferentiated carcinoma; Synap: synaptophysin.

NEC and SNUC

cal adenopathy or distant metastases at the time of presentation is an uncommon finding [1, 3, 28]. Computed tomography (CT) [22] and magnetic resonance imaging (MRI) should be performed in all cases of SNEC to evaluate the degree of local invasion of the primary tumor and the presence of cervical adenopathy, which guides the subsequent treatment planning. MRI is more important in differentiating tumor from inflammatory lesions and fluid retention. Well-differentiated tumors demonstrate a homogenous density or signal intensity. This is in contrast to moderate or poorly differentiated tumors that usually show a heterogeneous density or signal intensity. Con-

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Nicolai P, Bradley PJ (eds): Anterior Skull Base Tumors. Adv Otorhinolaryngol. Basel, Karger, 2020, vol 84, pp 168–184 (DOI: 10.1159/000457936)

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cavity [1, 8, 9]. SNEC usually presents with nonspecific sinonasal symptoms similar to any other benign or malignant lesions, like nasal obstruction, epistaxis, and facial pain. Poorly differentiated SNECs, like SmCNEC, are aggressive tumors and may demonstrate symptoms of local invasion into nearby structures, such as the orbit, skull base, brain, and nasopharynx-like proptosis and facial swelling [1, 9, 13]. Rarely, some cases of SmCNEC can present with paraneoplastic syndrome in the form of inappropriate antidiuretic hormone secretion (SIADA syndrome) or calcitonin secretion [25–27]. SNECs usually present at an advanced stage, with the majority usually presenting with T3 and T4 disease. Presence of cervi-

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diagnosis contribute to the inconsistency of the treatment approaches adopted for these tumors and the inability to develop a standardized treatment approach to such tumors. Treatment modalities for SNEC include surgery, radiotherapy, and chemotherapy. Multimodality treatment was recommended for the treatment of SNEC, especially SmCNEC, which is an extremely aggressive tumor and carries the worst outcome among all non-ONB neuroendocrine sinonasal malignancies [1, 31–33]. In a recent large meta-analysis study including 710 SNECs, surgery was the preferred treatment modality that can yield the best outcome regardless of the histological differentiation. The researchers believe that well-differentiated NEC can be treated with surgery as a monotherapy, while moderate, differentiated tumors require postoperative radiotherapy. For SmCNECs, although surgery shows a better outcome compared to those who did not undergo surgery, this difference did not reach statistical significance. The use of chemotherapy was not associated with improved survival. They found an improvement in treatment outcomes over the years, which might be explained by the increasing trend toward the use of multimodality instead of single modality treatment in addition to the advances in surgical techniques [6]. Many authors recommended the use of chemotherapy for SNEC. In their series of 28 patients treated for NEC, half were treated with surgery as the primary treatment, and chemoradiation (CRT) was utilized in one third of the cases, Mitchell et al. [1] found that a complete response to neoadjuvant chemotherapy could predict improved survival at 3 years (p < 0.005). These results are also similar to results from the University of North Carolina Chapel Hill, where a complete response to neoadjuvant CRT signifies a better prognostic outcome. Their preferred approach was neoadjuvant CRT followed by surgery [34]. The use of induction chemotherapy (IC) followed by either surgical resection or CRT based

Abdelmeguid/Bell/Hanna

Nicolai P, Bradley PJ (eds): Anterior Skull Base Tumors. Adv Otorhinolaryngol. Basel, Karger, 2020, vol 84, pp 168–184 (DOI: 10.1159/000457936)

Downloaded by: Stanford Univ. Med. Center 35.203.130.101 - 8/28/2020 5:04:02 PM

trast enhancement is usually demonstrated in all cases. In contrast to soft tissue NECs, SNECs usually appear as ill-defined and irregular lesions [29]. It appears as a hyperintense lesion in T1and T2-weighted imaging, with strong enhancement on T1-weighted images [30]. Overall, SNECs have a reasonable prognosis. The average 5-year overall survival (OS) is around 65%, while the average 5-year disease-specific survival (DSS) is about 70% [1, 3, 6]. However, the prognosis can vary considerably depending on the histological type and the degree of differentiation rather than the TNM staging [6]. In a recent report that focused only on the treatment of SNEC from the MD Anderson Cancer Center and included 28 patients with SNEC without separation between the different histological subtypes, the 5-year OS, DSS, and diseasefree survival were 66.9, 78.5, and 43.8%, respectively. The local, regional, and distant failure rates were reported to be 21, 25, and 18%, respectively [1]. On the other hand, SmCNECs, although extremely rare, are aggressive tumors with an inferior outcome when compared to other SNECs. The 5-year OS for SmCNEC was reported to be lower than 30% [3, 13], with high rates of local and regional recurrences (33 and 44%, respectively) [31]. A study that included 21 patients with SmCNEC from 8 different French institutes treated between 1989 and 2003 reported a very high recurrence rate of 48% (10/21) during the first 2 years. Nine of those patients died within the first 4 years, with only 1 patient surviving more than 10 years [13]. Predictors of poor survival outcomes of SNEC include origins outside the nasal cavity and the presence of bony, foveal, or orbital invasion [1]. Although the majority of cases usually present at an advanced stage, it has no impact on the prognosis and treatment planning [6]. As mentioned before, SNECs are extremely rare. Only a few cases have been reported in the literature, which together with the difficulties in

NEC and SNUC

the groups in terms of treatment outcomes, with multimodality treatment recommended in both groups [28]. On the other hand, a meta-analysis trying to answer the same question, including 701 patients with SNEC, found that well- and moderately differentiated SNECs have better outcomes and require a less aggressive treatment approach. They believe that surgery alone may be enough in well-differentiated SNEC, while moderate and poorly differentiated tumors require a multimodality approach comprising postoperative radiotherapy [6]. Sinonasal SmCNEC is very aggressive with a high rate of locoregional and distant failure. It has a high propensity to distant metastases of up to 75%. This aggressive behavior and poor outcome of SmCNEC necessitate the use of multimodality treatment with the need of systemic therapy in addition to radiation therapy. Prophylactic brain irradiation has been suggested to be included in the primary radiation field due to the high risk of brain metastases in patients with SmCNEC [3]. Elective neck treatment in SNEC is not clear in the literature. While some authors do not recommend elective neck treatment [13], others recommend doing so. Mitchell et al. [1] reported high rates of regional recurrence up to 25%, which may warrant the need for elective neck treatment alongside treatment of the primary tumor. This finding also correlates with the findings from another study where neck metastases developed among those who did not receive elective neck treatment in contrast to none among those who received elective neck treatment [28]. In a recent SEER database study that included 141 SNUCs and SmCNECs, there were high rates of initial nodal involvement including levels 2 and 3, and in some cases level 1, suggesting a benefit from elective treatment to those levels [35]. LCNEC was recognized as a separate entity from other types of NEC. Very few studies are available that tried to understand the behavior and outcomes of LCNEC, including a very limited number of cases that involve the sinonasal re-

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Nicolai P, Bradley PJ (eds): Anterior Skull Base Tumors. Adv Otorhinolaryngol. Basel, Karger, 2020, vol 84, pp 168–184 (DOI: 10.1159/000457936)

Downloaded by: Stanford Univ. Med. Center 35.203.130.101 - 8/28/2020 5:04:02 PM

on the response has been tried in some institutions with promising results. Among 19 patients with ONB and SNEC, where the response to the neoadjuvant chemotherapy was used to guide the subsequent treatment to either proton radiation therapy in good responders or surgery with postoperative proton radiotherapy in those who did not respond, the 5-year OS was 74% [31]. The use of this approach also added the advantage of avoiding the morbidity of craniofacial resection, with all of the patients who avoided surgery able to preserve their vision. The authors also concluded that a complete or partial response (PR) to chemotherapy can significantly predict better OS and metastases-free survival, although it has no considerable impact on the local recurrence. The main limitation of the study was that they combined both ONB and SNEC together, which might have created an overestimation of NEC survival. Bhattacharyya et al. [32] utilized the same approach of IC with encouraging results. Their prospective study of 9 patients included 5 with ONB and 4 with SNEC. They reported a dramatic response in the majority of cases (8 out of 9) without the need for surgery. They had no recurrence in their series, with a mean disease-free survival of 14 months without any major complications. However, this prospective trial was not able to histologically separate ONB from SNEC in relation to the outcome. As mentioned before, the degree of differentiation could be correlated with the clinical behavior and prognosis of NEC. In contrast to laryngeal NEC where differentiation guides the treatment approach, the paucity of studies and small number of cases involved in those studies make it difficult to establish the same concept in the treatment of SNEC. In a study trying to understand the impact of histological differentiation of SNEC on the clinical behavior and treatment outcomes, although moderately differentiated SNECs tend to be less aggressive than poorly differentiated ones, there was no significant difference between

Sinonasal Undifferentiated Carcinoma

SNUC is a rare aggressive malignancy that arises from the nose and paranasal sinuses and accounts for only 3–5% of all sinonasal cancers. Frierson et al. [37] described it for the first time in 1986, and it was believed to originate from the Schneiderian epithelium of the nose and paranasal sinuses [38– 40]. SNUC is a high-grade epithelial neoplasm with uncertain histogenesis with or without neuroendocrine differentiation but without evidence of squamous or glandular differentiation [37]. It was later redefined by the WHO as a highly aggressive and clinicopathologically distinctive carcinoma of uncertain histogenesis that typically presents as a local extensive disease. It was believed that SNUC originates from the Schneiderian epithelium of the nose and paranasal sinuses [41]. SNUC usually shows a slight male predominance (2–3: 1). The age at presentation ranges from the 3rd to 9th decade, with a median age at presentation of 50–60 years [41–43]. The presenting symptoms are variable and range from nonspecific nasal symptoms like nasal obstruction, epistaxis, facial pain, and headache, to severe visual symptoms (proptosis, diplopia, and impaired visual acuity) and cranial nerve palsies. The dura-

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tion of symptoms is usually short (from weeks to months). SNUC usually presents at an advanced stage, with more than 65% staged as T4 with extensive local invasion. Involvement of the skull base, orbit, and intracranial invasion are common findings [43–47]. Approximately 10–30% of SNUC patients have evidence of cervical lymph node metastases at the time of presentation, while distant metastases are an uncommon finding at the initial presentation [48]. A combination of CT and MRI is required to assess the degree of local invasion of the tumor and also to assess the presence of cervical adenopathy. Additional imaging like positron emission tomography and CT chest may be utilized to assess the presence of distant metastasis [42]. Patients are usually staged according to the American joint Committee on Cancer (AJCC) staging system. However, the Kadish staging system that was developed originally to classify ONB and correlated with 5-year survival was used by some authors to describe the extent of SNUC [49, 50]. Microscopically, SNUC is formed of nests, lobules, trabeculae, and sheets of medium-sized cells without squamous differentiation [37, 51] (Fig. 6). Severe dysplasia of the overlying epithelium may be observed [41, 52]. Ulceration is usually seen which precludes the epithelial origin o...